Project Summary/Abstract This is a continuing investigation of synaptic transmission in vestibular organs with particular emphasis on the type I hair cell and its calyx ending, phylogenetically recent acquisitions, only found in reptiles, birds and mammals. These structures are restricted to central/striolar zones In reptiles and birds. Their increasing importance in mammals is suggested by their distribution throughout the neuroepithelium of all organs. In addition, while type I and type II hair cells occur in approximately equal numbers in rodent cristae, type I hair cells predominate in the cristae of monkeys and possibly of humans. The peculiar structure and distinctive physiology of type I hair cells and their calyx endings raise problems as to the mechanisms of synaptic transmission between these structures. 1) Type I hair cells have a distinctive basolateral current that may compromise synaptic transmission;2) housekeeping functions cannot be done by supporting cells;and 3) the geometry and electrophysiology of the calyx ending place unusual demands on the flow of synaptic currents to the spike encoder. We have only fragmentary knowledge as to how the type I hair cell and its ending solve the problems posed by these distinctive features. Yet, because these structures become of increasing importance in mammals (including humans), such knowledge is crucial to our understanding as to how vestibular organs process information. Of clinical interest, the type I hair cell and/or its calyx ending are especially sensitive to aminoglycoside ototoxicityand age-related degeneration. Physiological studies will be done in the turtle posterior crista and will be integrated with morphological/molecular studies to be done in rats and turtles. We propose to test three specific hypotheses. 1) Hair cells: We have evidence that the distinctive type I current (IK,L) does not impede neurotransmitter release. The hypothesis is that signal-transduction pathways modulate IK.L so that it no longer impedes quantal transmission. 2) Housekeeping: Both K+ ions and glutamate neurotransmitter are released from hair cells during transduction. In the case of type II hair cells, supporting cells do the necessary job of clearing these substances. The presence of the calyx ending precludes supporting cells from acting in the same way for type I hair cells. We hypothesize that the type I hair cell and/or its ending subsume these housekeeping functions. 3) Postsynaptic mechanisms: Concerning the calyx ending, the hypothesis to be tested is that the molecular organization of the calyx creates separate microdomains with discrete functions: synaptic transmission, spike initiation, and discharge regularity..